The present invention is directed to an oral dosage form for administration to a warm blooded animal of the combination of tegafur, uracil, and folinic acid to potentiate coadministered oxaliplatin for the treatment of tumors.
5-Fluorouracil (5-FU) is a known anti-tumor agent. The combination of 5-fluorouracil and folinic acid is a known treatment for colorectal cancer. Tegafur (1-(2-tetrahydrofuryl)-5-fluorouracil) is a prodrug of 5-fluorouracil. In vivo, 5-fluorouracil is rapidly inactivated by the enzyme dihydropyridine dehydrogenase (DPD). Uracil competitively inhibits DPD metabolism of 5-FU generated from tegafur. Thus, coadministration of uracil with tegafur results in higher exposures of active 5-FU as compared to tegafur alone. It is known that 5-fluorouracil cannot be administered orally.
U.S. Pat. No. 4,328,229 discloses an anti-cancer composition containing 1-(2-tetrahydrofuryl)-5-fluorouracil (xe2x80x9ctegafurxe2x80x9d) and uracil. The composition is used for delivery of 5-fluorouracil to a cancer sensitive to 5-fluorouracil in a warm-blooded animal. It is disclosed that the composition can be administered in a variety of dosage forms including an oral dosage form.
U.S. Pat. No. 5,534,513 discloses an anti-tumor composition containing tegafur and uracil in a molar ratio of 1:4. This anti-tumor composition is stated to be further potentiated by the administration of folinic acid or a pharmaceutically acceptable salt thereof. It is disclosed in the ""513 patent that the combination can be administered in a variety of dosage forms including an oral dosage form.
Oxaliplatin (C8H14N2O4Pt, [(1R, 2R)-1,2-cyclohexanediamine-N,Nxe2x80x2][oxalato(2-)-O, Oxe2x80x2]platinum) is a diaminocyclohexane compound that is known to cause DNA damage of the same sites of adduct formation as does cisplatin. Oxaliplatin has been used to treat various tumors including some that are resistant to cisplatin.
It has been observed that 5-fluorouracil can enhance the activity of oxaliplatin. However, because 5-fluorouracil cannot be administered orally, the mode of administration for this combination therapy requires a more invasive form of administration such as by intravenous injection, and therefore typically requires administration by trained medical personnel.
It would be an advance in the art of treating tumors, especially colorectal cancerous tumors, if a therapy could be developed employing a potentiated form of oxaliplatin through the action of 5-fluorouracil in a convenient dosage form for oral administration.
The present invention is directed to a dosage form suitable for oral administration to a mammal for the treatment of tumors, especially colorectal tumors, that exhibits a synergistically enhanced effect in combination with oxaliplatin. In particular, there is provided in accordance with the present invention a dosage form suitable for oral administration to a mammal having a tumor comprising an effective amount of each of tegafur, uracil, and folinic acid or a pharmaceutically acceptable salt thereof to a patient undergoing treatment with oxaliplatin, wherein said dosage form is a potentiator of oxaliplatin. In a preferred form of the invention, tegafur and uracil are present in respective amounts sufficient for tegafur to effectively and efficiently convert to 5-fluorouracil. In a particularly preferred form of the invention tegafur and uracil are present in a molar ratio of about 1:4 (hereinafter referred to as xe2x80x9cUFTxe2x80x9d).
There is also disclosed a method of orally administering an anti-tumor effective amount of the combination of tegafur and uracil, preferably as UFT, and folinic acid or a pharmaceutically acceptable salt thereof to a mammal having a tumor who is undergoing oxaliplatin therapy.
The present invention further provides a method for the synergistic treatment of cancer, such as colorectal cancer, which comprises orally administering a synergistically effective amount of tegafur, uracil, and folinic acid or a pharmaceutically acceptable salt thereof, such as calcium folinate, to a mammal undergoing treatment with oxaliplatin.